M ILITARY M EDICINE, 180, 6:621, 2015
Relationship Between Toxoplasma gondii and Mood Disturbance in Women Veterans Ally son R. Duffy, PhD, RN*§; Theresa M. Beckie, PhD, RN, FAHA*; Lisa A. Brenner, PhD, ABPPf, Jason W. Beckstead, PhD**§ ; Andreas Seyfang, PhDf; Teodor T. Postolache, MD H JI**; Maureen W. Groer, PhD, RN, FAAN*f
A B ST R A C T Background: Toxoplasma gondii is an intracellular protozoan parasite with zoonotic potential that causes acute and chronic diseases, which has been associated with schizophrenia, depression, bipolar disorder, and suicidal behavior. Military personnel may be at increased risk for exposure to the parasite when deployed to countries with high prevalence rates. Methods: Women Veterans were recruited to participate in the study at an event to recognize women Vet erans and later through e-mails. Blood samples were collected from 70 women Veterans (mean age: 47 years) and analyzed for T. gondii IgG titer. Participants completed a demographic instrument, Center for Epidemiologic Studies Depression scale, Profile of Mood States (POMS), and Post-Traumatic Stress Disorder Checklist-Military. Results: The infectivity rate was lower than the rate in the United States (11.4% [8 out of 70 were seropositive], but 6 of the 8 [75%] had been deployed outside the United States. Pearson correlations and t tests showed significant relationships between T. gondii seropositivity and Center for Epidemiologic Studies Depression score), POMS-depression, POMS-confusion, and POMS-anger subscale scores, and total mood disturbance score. Conclusions: This study is the first to describe biobehavioral rela tionships between chronic T. gondii infection, depression, and dysphoric moods in a military veteran population.
INTRODUCTION Toxoplasma gondii, an intracellular protozoan parasite, is one of the most common parasites infecting approximately one-third of the world’s population.1 The seroprevalence rate of toxoplasmosis is estimated to be between 20% and 80% worldwide, with the most common form a latent state in which intracellular organisms (bradyzoites) form small cysts ringed with inflammatory cells and exudate in the brain, and skeletal and cardiac muscles.2 In 2009 to 2010, the overall T. gondii antibody seroprevalence was 13.2% and ageadjusted seroprevalence was 12.4%; age-adjusted seropreva lence among women of age 15 to 44 years was 9.1%. The ♦University of South Florida College of Nursing, 12901 Bruce B Downs Boulevard, Tampa, FL 33612. •[University of South Florida College of Medicine, 12901 Bruce B Downs Boulevard, Tampa, FL 33612. ^Veterans Integrated Service Network (VISN) 19 Mental Illness Research, Education and Clinical Center (MIRECC); and Departments of Psychiatry, Neurology, and Physical Medicine and Rehabiliation, University of Colorado, Anschutz Medical Campus, 1055 Clermont Street, Denver, CO 80220. §Veterans Integrated Service Network (VISN) 8 Center of Innovation on Disability and Rehabilitation Research (CINDER), James A. Haley Veterans Hospital, 8900 Grand Oak Circle Tampa, FL 33637. || Veterans Integrated Service Network (VISN) 19 Rocky Mountain Mental Illness Research, Education and Clinical Center (MIRECC), 1055 Clermont Street Denver, CO 80220. ][Mood and Anxiety Program, University of Maryland School of Medi cine, 685 West Baltimore Street, Room 930, Baltimore, MD 21201. ♦♦Capitol Healthcare Veterans Integrated Service Network (VISN) 5, Mental Illness Research Education and Clinical Center (MIRECC), Baltimore, MD, USA. The views presented here belong to the authors and cannot be con strued as official opinions of the Department of Veteran Affairs or of the Department of Defense. doi: 10.7205/MILMED-D-14-00488
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prevalence of T. gondii antibody is still common worldwide. However, the prevalence in the United States has continued to decline.2 T. gondii oocytes are reproduced only in the intestine of cats. Any warm-blooded mammal or bird may be the inter mediate host of the parasite by becoming infected through exposure to oocytes directly (including consumption of con taminated water or unwashed vegetables), or by consuming infected meat containing T. gondii tissue cysts (bradyzoites). Once the parasite has infected an intermediate host, an acute infection ensues, which can be either asymptomatic or have flu-like symptoms. After the initial, acute infection, cysts containing bradyzoites are formed that can be found in vari ous tissues in the host’s body, including skeletal muscle and brain tissue.2 Until recently, the chronic phase of the infection was thought to be asymptomatic. However, mood and behavior changes have now been reported in both animals and humans during this period of latency.1'4'5 A positive T. gondii anti body titer is associated with changes in personality6'7 and psychiatric disorders, such as schizophrenia,7-9 depression,10 bipolar disorder,11-13 and suicidal behavior4’8'14’15 Other behavioral manifestations include risk-taking, delayed reac tion time, and reduced neural processing speed.16 This may explain the reason that traffic accidents are increased in sero positive individuals.1718 In rodents, a reversal in avoidance of cat odor and an attraction instead has been reported.19,20 Although mechanisms are unclear, underlying changes in per sonality and behavior in rodents may occur as a result of the local inflammatory response induced by T. gondii neural cysts.21 Approximately 14% of military personnel are women who have been deployed in support of Operations Enduring Freedom and Iraqi Freedom (OEF/OIF), with increasing
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exposure to combat situations.22 Psychological distress result ing from deployment to war zones among male Veterans has been studied extensively; however, research regarding women Veterans is limited. Military personnel are at a higher risk for developing post-traumatic stress disorder (PTSD), depression, and increased risk for suicide.21'24 In addition, anger, hos tility, and aggression have been found in service members returning home from deployments.25 26 Higher levels of posttraumatic and depressive symptoms have been found in women Veterans who reported combat exposure.27'28 Although these psychological disturbances may be highly associated with the experience of war-related trauma, other factors of potential significance that may create additional vulnerability, such as infection with latency-establishing neurotropic micro organisms such as T. gondii, have not been examined. Virtually nothing is known about possible relationships of Veterans psychological illnesses such as PTSD and depres sion and T. gondii serological status. Because of our group’s interest in women Veterans health, we conducted a preliminary, cross-sectional study. Specifi cally, we asked the question: Is there a relationship between positive T. gondii IgG titers and deployment, mood distur bances, depression, and PTSD symptoms in women Veterans? METHODS
Participants The study was approved by the University of South Florida Institutional Review Board and the Department of the Army review board, Telemedicine and Advanced Technology Research Center, and written informed consent was obtained before participation. Three-quarters of the sample were recruited at a widely advertised day of recognition for women Veterans event in 2011 and the remainder was recruited through e-mail and personal contacts through 2013. Participants had to be English-speaking Veterans with the ability to read at an 8th grade level. Participating women received a $50 gift card.
Instruments The investigator-developed demographic questionnaire included variables such as age; race and ethnicity; marital status; and health, medication, and deployment history. The Profile of Mood States (POMS) is a 65-item instru ment used to measure dysphoric moods, and includes 7 sub scales: anger-hostility, tension-anxiety, depression-dejection, confusion-bewilderment, fatigue-inertia, vigor-activity, and a total mood disturbance. The POMS has yielded data with adequate reliability in a number of studies, ranging from 0.63 (confusion) to 0.96 (depression).29 Evidence of concur rent validity was demonstrated with significant Pearson cor relations among the POMS-depression scale and the Beck Depression Index (r = 0.81).10 The Center for Epidemiologic Studies Depression (CES-D) scale is a 20-item, summated rating, self-report questionnaire that is widely used to assess depressive symptoms.11 A
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cutoff score above 16, though not diagnostic, has been highly correlated with clinical depression.12 The correlations between the CES-D items and total score have been reported to range from 0.40 to 0.70.3114 Evidence of reliability of the CES-D was provided by a high total scale Cronbach a of 0.88 for women in middle age35 and 0.96 for women Vet erans returning from Iraq and Afghanistan.36 In addition, internal consistency was also assessed in a population of soldiers returning from combat operations in both OIF and OEF with a of 0.92 and 0.93, respectively.37 The PTSD Checklist-Military (PCL-M) is a 17-item checklist that asks about symptoms in response to stressful military experiences.38 It has evidence of validity and reli ability, and serves as a brief screening instrument for PTSD symptom, but it is not diagnostic. Items are weighted and summed for a total score ranging from 17 to 85. There are multiple scales available for screening PTSD symptoms and the PCL-M has been used in many studies of military populations. Although generally considered to be a good screening device, it has been critiqued as not being specific to the disorder but rather measuring general distress.39’40
T. gondii Titers Participants’ blood samples were collected at the Veterans rec ognition event or at individual appointments. Blood was col lected in heparinized tubes and transported to the University of South Florida College of Nursing Biobehavioral laboratory in a chilled cooler. Blood samples were centrifuged at 400 g for 25 minutes at 4°C. Plasma was removed by pipette, and placed in Eppendorf tubes for storage at -80°C until assayed for T. gondii IgG. The samples were analyzed by enzyme-linked immunosorbent assay (Diagnostic Automation, Calabasas, California) that tests for levels of Immunoglobulin G to whole tachyzoites. Positivity in the kit used was determined by a titer of 20 IUs or greater. All positive samples and a subset of negative samples were also tested for IgM antibodies to T. gondii by enzyme-linked immunosorbent assay (ABCAM, Cambridge, Massachusetts) to rule out recent infection.
Data Analysis Based on the skewness of the T. gondii IgG titer data, values were logl0 transformed for parametric analyses. The cut point defining positive titer (and therefore infection) of 20 IUs was used for this analysis. Chi-square and r-tests were conducted to examine relationships between T. gondii antibody titers and the other variables of interest. Because of the small number of women who tested positive for T. gondii, multivar iate approaches were not feasible. SPSS version 20 (SPSS, Chicago, Illinois) was used for statistical analysis. RESULTS
Participants There were 79 women Veterans who participated in this study, but complete data were available for 70. The sample
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was composed of Caucasians (60%), African Americans (26%), and 16% Hispanics with a mean age of 47 ± 10.5 years (range 24-71 years). Twenty-seven participants (38.6%) reported that they were married, 24 (34.3%) divorced, 12 (17.1%) single or never married, 5 (7.1%) widowed, and 2 (2.9%) separated. Annual income ranged from under $15,000 (15.8%), $15,000 to $25,000 (9.2%), $25,000 to $40,000 (22.4%), $40,000 to $70,000 (23.7%) and over $70,000 (28.9%). This was a highly educated sample, with only 4 participants without a collegiate or graduate education. Thirty-four participants (48.6%) reported previous deployment with 56% deployed to the Middle East. Fifteen participants had more than one deployment, and three had three or more deployments. Deployment history time frame ranged from 1980 to 2010. For the purposes of this study, deployment was defined as any assignment out of the United States, regardless of the country or operation. P s y c h o s o c ia l a n d P s y c h o lo g ic a l M e a s u re s
The mean score on the POMS-total mood disturbance score was 26.91 (SD = 41.69, ranging from 0 to 142). Mean score on the CES-D was 18.10 (SD = 47.06, ranging from 0 to 45). A score above 16 is indicative of depressive symptom atology and 35 (50%) participants had CES-D scores of 16 or higher. The mean score on the PCL-M was 35.87 (SD = 18.41) with scores ranging from 17 to 77. Higher scores were found in those who had been deployed. T. gondii IgG and IgM antibody titers in this sample were analyzed on all 70 participants. The mean T. gondii IgG titer was 18.03 IU (SD = 47.06) with a range of 1.66 to 227.01. Eight participants (11.42%) had IgG titers above the cut point for seropositivity. The mean titer for these women (n = 8) was 126 IU/mL ± 81.04. The IgM titer was negative for all cases. R e la tio n s h ip s W ith S e ro p o s itiv ity
The relationship between T. gondii IgG seropositivity and ethnicity was statistically significant, / 2 (df = 1, n = 70) = 11.90, p < 0.05. Four of the 8 (50%) seropositive women Veterans were Hispanic, whereas only 4 of 62 (6.5%) nega tive women reported this ethnicity. The relationship between T. gondii and education level was also significant, (d f = 4, n = 46) = 9.24, p < 0.05, with T. gondii-positive women less likely to have completed higher levels of education than negative women, or higher than a Bachelor’s degree. Partici pants with positive T. gondii antibody titers (51.7 years old) were older than those with a negative T. gondii antibody titer (46.8 years), but this was not significant. There was no relationship between income levels and T. gondii seropositiv ity. Seven out of the 8 participants with a positive T. gondii antibody titer reported that their highest military rank was achieved when enlisted. Pearson correlations (r) were calculated on the total range of T. gondii IgG titers, CES-D scores, PCL-M scores, and
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POMS scores, both total score and subscales. T. gondii IgG titers were significantly correlated with the POMS-depression subscale, r = 0.245, n = 70, p < 0.05; POMS-confusion/ bewilderment subscale, r = 0.242, n = 70, p < 0.05; and POMS-total subscale, r = 0.292, n = 70, p < 0.05; and were also correlated significantly with the CES-D scores, r = 0.224, p < 0.05. Although these results are significant, the effects appear to be small. To analyze the differences in mood disturbance between positive and negative women, r-tests were conducted com paring these two groups. Seropositive participants had sig nificantly higher POMS-depression scores (t (68) = 2.35, p < 0.05) with an effect size (rj2) of 0.08, higher POMStension scores (t (68) = 2.06, p < 0.05, t f = 0.06), and higher POMS-anger scores (t (68) = 2.18, p < 0.05, rf = 0.07). The CES-D score was significantly higher in seroposi tive women (t (68) = 2.68, p = 0.026, t f = 0.09). There were no significant differences in PCL-M scores between the 2 groups. Cronbach a was calculated for each instrument analyzed in this study and there was an evidence of good to excellent internal consistency in these data (CES-D = 0.90, PCL = 0.96, POMS depression = 0.94, POMS tension = 0.93, POMS anger = 0.94, POMS confusion = 0.74, POMS fatigue = 0.94, POMS total = 0.91).
DISCUSSION The purpose of this study was to examine the relationships between sociodemographic variables, deployment, mood, depression, PTSD symptoms, and T. gondii IgG antibody titer. There is almost no literature about incidence, risk fac tors, and effects of T. gondii infection in military populations, especially in women Veterans. However, military recruits were measured for T. gondii IgG titer in 196241 and again in 198 942 as a general proxy for U.S. population levels. Smith et al42 reported a decrease in seropositivity for T. gondii by one-third over the past 27 years in these not-yet-deployed military recruits. Previous studies support our findings of relationships between T. gondii antibody titer and psychiatric symptoms and behavior. Several studies show that suicide attempters had significantly higher T. gondii IgG antibody titers4,8,15’43' 45 T. gondii seroprevalence has also been recently reported to be related to bipolar disorder." Groer et al'° reported a posi tive correlation of T. gondii IgG antibody titer with POMSdepression and POMS-anxiety subscale scores in a sample of 414 pregnant women, 44 of whom were seropositive for T. gondii infection. Amminger et al46 reported in 105 partic ipants a high risk for psychosis that higher levels of T. gondii IgG antibodies were significantly associated with more severe positive psychotic symptoms. T. gondii infection has also been linked to psychiatric disorders such as schizophrenia47 and bipolar disorder." The relationships between T. gondii and depressive symptoms, anger, confusion, and overall mood disturbance
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that were found in this study are particularly important because it has been reported that individuals infected by T. gondii have a higher risk of suicidal behavior. This rela tionship is troubling, particularly in Veterans, as they have an increased risk for suicide. With the number of suicides increasing annually across all branches of the military, both in active duty service members and in Veterans, the role of T. gondii infections deserves further exploration. Potential explanations must be considered in regard to the relationships between T. gondii and mood disturbance. Per haps depression and dysphoria lead to behaviors such as poor hygiene habits that can increase exposure and infection. In addition, genetic differences in susceptibilities may be involved.48 Some studies suggest that the T. gondii link with depression is only present in bipolar disease and not unipolar depression. 11 There may be corelationships of T. gondii infection with other neurotropic organisms. Nevertheless the remarkable relationships we have observed underscore the interest for further exploration with larger sample sizes. Hence, a larger sample size recruited from a broader geo graphical area will be needed to add additional power and allow generalizing of the results more widely. Similarly, it would be important to include male Veterans in further stud ies as well. Recruitment of participants in this study (women Veterans’ event and personal contacts) posed a risk of poten tial selection bias. The association of mood disturbance and depression with T. gondii IgG titer in this small sample sup ports the neuroinflammation hypothesis; however, inflamma tory markers were not measured to test that relationship. The low number of women Veterans who were seroposi tive for T. gondii reduced the ability to control for age and ethnicity. Titers below the cut point for seropositivity may indicate resolved infection in the distant past and this was not possible to evaluate. Current latent infection with T. gondii was most prevalent in women who had been deployed to foreign countries. Future follow-up studies to further investi gate the results of this study should include larger sample sizes, younger age distribution with recent deployment to Iraq and Afghanistan, measurement of both IgG and IgM titers including antibody affinity and serotyping to determine timing and source of infection, longitudinal sampling of individuals, examination of lifestyle factors (diet, exposure to feral cats, hygiene) of individuals while deployed, and appropriate demographic controls, as well as, potentially, functional neuroimaging and neuropsychological testing. ACKNOWLEDGMENTS This material is based on the work supported by the Office of Research and Development, Health Services R&D Service, Department of Veterans Affairs (RRP 06-151). We are extremely grateful to the women Veterans who par ticipated in this study. We are also grateful for the students and faculty who volunteered their time at the Women Veterans’ Day of Recognition held on November 2011 as well as the laboratory staff at the University of South Florida College of Nursing Biobehavioral laboratory. This article was devel oped through grant funding support from Research to Improve Emotional Health and Quality of Life Among Service Members with Disabilities
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(RESTORE LIVES) Department of the Army grant number W81XWH-101-0719. The sponsors had no role in the collection of study data or preparation, review, or approval of the manuscript. Dr. Brenner's and Dr. Postolache’s contributions were supported by the Rocky Mountain MIRECC, VISN 19, Denver, CO. Additionally, Dr. Postolache was sup ported by the American Foundation for Suicide Prevention (Distinguished Investigator Award).
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Relationship Between Toxoplasma gondii and Mood Disturbance in Women Veterans Ally son R. Duffy, PhD, RN*§; Theresa M. Beckie, PhD, RN, FAHA*; Lisa A. Brenner, PhD, ABPPf, Jason W. Beckstead, PhD**§ ; Andreas Seyfang, PhDf; Teodor T. Postolache, MD H JI**; Maureen W. Groer, PhD, RN, FAAN*f
A B ST R A C T Background: Toxoplasma gondii is an intracellular protozoan parasite with zoonotic potential that causes acute and chronic diseases, which has been associated with schizophrenia, depression, bipolar disorder, and suicidal behavior. Military personnel may be at increased risk for exposure to the parasite when deployed to countries with high prevalence rates. Methods: Women Veterans were recruited to participate in the study at an event to recognize women Vet erans and later through e-mails. Blood samples were collected from 70 women Veterans (mean age: 47 years) and analyzed for T. gondii IgG titer. Participants completed a demographic instrument, Center for Epidemiologic Studies Depression scale, Profile of Mood States (POMS), and Post-Traumatic Stress Disorder Checklist-Military. Results: The infectivity rate was lower than the rate in the United States (11.4% [8 out of 70 were seropositive], but 6 of the 8 [75%] had been deployed outside the United States. Pearson correlations and t tests showed significant relationships between T. gondii seropositivity and Center for Epidemiologic Studies Depression score), POMS-depression, POMS-confusion, and POMS-anger subscale scores, and total mood disturbance score. Conclusions: This study is the first to describe biobehavioral rela tionships between chronic T. gondii infection, depression, and dysphoric moods in a military veteran population.
INTRODUCTION Toxoplasma gondii, an intracellular protozoan parasite, is one of the most common parasites infecting approximately one-third of the world’s population.1 The seroprevalence rate of toxoplasmosis is estimated to be between 20% and 80% worldwide, with the most common form a latent state in which intracellular organisms (bradyzoites) form small cysts ringed with inflammatory cells and exudate in the brain, and skeletal and cardiac muscles.2 In 2009 to 2010, the overall T. gondii antibody seroprevalence was 13.2% and ageadjusted seroprevalence was 12.4%; age-adjusted seropreva lence among women of age 15 to 44 years was 9.1%. The ♦University of South Florida College of Nursing, 12901 Bruce B Downs Boulevard, Tampa, FL 33612. •[University of South Florida College of Medicine, 12901 Bruce B Downs Boulevard, Tampa, FL 33612. ^Veterans Integrated Service Network (VISN) 19 Mental Illness Research, Education and Clinical Center (MIRECC); and Departments of Psychiatry, Neurology, and Physical Medicine and Rehabiliation, University of Colorado, Anschutz Medical Campus, 1055 Clermont Street, Denver, CO 80220. §Veterans Integrated Service Network (VISN) 8 Center of Innovation on Disability and Rehabilitation Research (CINDER), James A. Haley Veterans Hospital, 8900 Grand Oak Circle Tampa, FL 33637. || Veterans Integrated Service Network (VISN) 19 Rocky Mountain Mental Illness Research, Education and Clinical Center (MIRECC), 1055 Clermont Street Denver, CO 80220. ][Mood and Anxiety Program, University of Maryland School of Medi cine, 685 West Baltimore Street, Room 930, Baltimore, MD 21201. ♦♦Capitol Healthcare Veterans Integrated Service Network (VISN) 5, Mental Illness Research Education and Clinical Center (MIRECC), Baltimore, MD, USA. The views presented here belong to the authors and cannot be con strued as official opinions of the Department of Veteran Affairs or of the Department of Defense. doi: 10.7205/MILMED-D-14-00488
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prevalence of T. gondii antibody is still common worldwide. However, the prevalence in the United States has continued to decline.2 T. gondii oocytes are reproduced only in the intestine of cats. Any warm-blooded mammal or bird may be the inter mediate host of the parasite by becoming infected through exposure to oocytes directly (including consumption of con taminated water or unwashed vegetables), or by consuming infected meat containing T. gondii tissue cysts (bradyzoites). Once the parasite has infected an intermediate host, an acute infection ensues, which can be either asymptomatic or have flu-like symptoms. After the initial, acute infection, cysts containing bradyzoites are formed that can be found in vari ous tissues in the host’s body, including skeletal muscle and brain tissue.2 Until recently, the chronic phase of the infection was thought to be asymptomatic. However, mood and behavior changes have now been reported in both animals and humans during this period of latency.1'4'5 A positive T. gondii anti body titer is associated with changes in personality6'7 and psychiatric disorders, such as schizophrenia,7-9 depression,10 bipolar disorder,11-13 and suicidal behavior4’8'14’15 Other behavioral manifestations include risk-taking, delayed reac tion time, and reduced neural processing speed.16 This may explain the reason that traffic accidents are increased in sero positive individuals.1718 In rodents, a reversal in avoidance of cat odor and an attraction instead has been reported.19,20 Although mechanisms are unclear, underlying changes in per sonality and behavior in rodents may occur as a result of the local inflammatory response induced by T. gondii neural cysts.21 Approximately 14% of military personnel are women who have been deployed in support of Operations Enduring Freedom and Iraqi Freedom (OEF/OIF), with increasing
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exposure to combat situations.22 Psychological distress result ing from deployment to war zones among male Veterans has been studied extensively; however, research regarding women Veterans is limited. Military personnel are at a higher risk for developing post-traumatic stress disorder (PTSD), depression, and increased risk for suicide.21'24 In addition, anger, hos tility, and aggression have been found in service members returning home from deployments.25 26 Higher levels of posttraumatic and depressive symptoms have been found in women Veterans who reported combat exposure.27'28 Although these psychological disturbances may be highly associated with the experience of war-related trauma, other factors of potential significance that may create additional vulnerability, such as infection with latency-establishing neurotropic micro organisms such as T. gondii, have not been examined. Virtually nothing is known about possible relationships of Veterans psychological illnesses such as PTSD and depres sion and T. gondii serological status. Because of our group’s interest in women Veterans health, we conducted a preliminary, cross-sectional study. Specifi cally, we asked the question: Is there a relationship between positive T. gondii IgG titers and deployment, mood distur bances, depression, and PTSD symptoms in women Veterans? METHODS
Participants The study was approved by the University of South Florida Institutional Review Board and the Department of the Army review board, Telemedicine and Advanced Technology Research Center, and written informed consent was obtained before participation. Three-quarters of the sample were recruited at a widely advertised day of recognition for women Veterans event in 2011 and the remainder was recruited through e-mail and personal contacts through 2013. Participants had to be English-speaking Veterans with the ability to read at an 8th grade level. Participating women received a $50 gift card.
Instruments The investigator-developed demographic questionnaire included variables such as age; race and ethnicity; marital status; and health, medication, and deployment history. The Profile of Mood States (POMS) is a 65-item instru ment used to measure dysphoric moods, and includes 7 sub scales: anger-hostility, tension-anxiety, depression-dejection, confusion-bewilderment, fatigue-inertia, vigor-activity, and a total mood disturbance. The POMS has yielded data with adequate reliability in a number of studies, ranging from 0.63 (confusion) to 0.96 (depression).29 Evidence of concur rent validity was demonstrated with significant Pearson cor relations among the POMS-depression scale and the Beck Depression Index (r = 0.81).10 The Center for Epidemiologic Studies Depression (CES-D) scale is a 20-item, summated rating, self-report questionnaire that is widely used to assess depressive symptoms.11 A
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cutoff score above 16, though not diagnostic, has been highly correlated with clinical depression.12 The correlations between the CES-D items and total score have been reported to range from 0.40 to 0.70.3114 Evidence of reliability of the CES-D was provided by a high total scale Cronbach a of 0.88 for women in middle age35 and 0.96 for women Vet erans returning from Iraq and Afghanistan.36 In addition, internal consistency was also assessed in a population of soldiers returning from combat operations in both OIF and OEF with a of 0.92 and 0.93, respectively.37 The PTSD Checklist-Military (PCL-M) is a 17-item checklist that asks about symptoms in response to stressful military experiences.38 It has evidence of validity and reli ability, and serves as a brief screening instrument for PTSD symptom, but it is not diagnostic. Items are weighted and summed for a total score ranging from 17 to 85. There are multiple scales available for screening PTSD symptoms and the PCL-M has been used in many studies of military populations. Although generally considered to be a good screening device, it has been critiqued as not being specific to the disorder but rather measuring general distress.39’40
T. gondii Titers Participants’ blood samples were collected at the Veterans rec ognition event or at individual appointments. Blood was col lected in heparinized tubes and transported to the University of South Florida College of Nursing Biobehavioral laboratory in a chilled cooler. Blood samples were centrifuged at 400 g for 25 minutes at 4°C. Plasma was removed by pipette, and placed in Eppendorf tubes for storage at -80°C until assayed for T. gondii IgG. The samples were analyzed by enzyme-linked immunosorbent assay (Diagnostic Automation, Calabasas, California) that tests for levels of Immunoglobulin G to whole tachyzoites. Positivity in the kit used was determined by a titer of 20 IUs or greater. All positive samples and a subset of negative samples were also tested for IgM antibodies to T. gondii by enzyme-linked immunosorbent assay (ABCAM, Cambridge, Massachusetts) to rule out recent infection.
Data Analysis Based on the skewness of the T. gondii IgG titer data, values were logl0 transformed for parametric analyses. The cut point defining positive titer (and therefore infection) of 20 IUs was used for this analysis. Chi-square and r-tests were conducted to examine relationships between T. gondii antibody titers and the other variables of interest. Because of the small number of women who tested positive for T. gondii, multivar iate approaches were not feasible. SPSS version 20 (SPSS, Chicago, Illinois) was used for statistical analysis. RESULTS
Participants There were 79 women Veterans who participated in this study, but complete data were available for 70. The sample
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was composed of Caucasians (60%), African Americans (26%), and 16% Hispanics with a mean age of 47 ± 10.5 years (range 24-71 years). Twenty-seven participants (38.6%) reported that they were married, 24 (34.3%) divorced, 12 (17.1%) single or never married, 5 (7.1%) widowed, and 2 (2.9%) separated. Annual income ranged from under $15,000 (15.8%), $15,000 to $25,000 (9.2%), $25,000 to $40,000 (22.4%), $40,000 to $70,000 (23.7%) and over $70,000 (28.9%). This was a highly educated sample, with only 4 participants without a collegiate or graduate education. Thirty-four participants (48.6%) reported previous deployment with 56% deployed to the Middle East. Fifteen participants had more than one deployment, and three had three or more deployments. Deployment history time frame ranged from 1980 to 2010. For the purposes of this study, deployment was defined as any assignment out of the United States, regardless of the country or operation. P s y c h o s o c ia l a n d P s y c h o lo g ic a l M e a s u re s
The mean score on the POMS-total mood disturbance score was 26.91 (SD = 41.69, ranging from 0 to 142). Mean score on the CES-D was 18.10 (SD = 47.06, ranging from 0 to 45). A score above 16 is indicative of depressive symptom atology and 35 (50%) participants had CES-D scores of 16 or higher. The mean score on the PCL-M was 35.87 (SD = 18.41) with scores ranging from 17 to 77. Higher scores were found in those who had been deployed. T. gondii IgG and IgM antibody titers in this sample were analyzed on all 70 participants. The mean T. gondii IgG titer was 18.03 IU (SD = 47.06) with a range of 1.66 to 227.01. Eight participants (11.42%) had IgG titers above the cut point for seropositivity. The mean titer for these women (n = 8) was 126 IU/mL ± 81.04. The IgM titer was negative for all cases. R e la tio n s h ip s W ith S e ro p o s itiv ity
The relationship between T. gondii IgG seropositivity and ethnicity was statistically significant, / 2 (df = 1, n = 70) = 11.90, p < 0.05. Four of the 8 (50%) seropositive women Veterans were Hispanic, whereas only 4 of 62 (6.5%) nega tive women reported this ethnicity. The relationship between T. gondii and education level was also significant, (d f = 4, n = 46) = 9.24, p < 0.05, with T. gondii-positive women less likely to have completed higher levels of education than negative women, or higher than a Bachelor’s degree. Partici pants with positive T. gondii antibody titers (51.7 years old) were older than those with a negative T. gondii antibody titer (46.8 years), but this was not significant. There was no relationship between income levels and T. gondii seropositiv ity. Seven out of the 8 participants with a positive T. gondii antibody titer reported that their highest military rank was achieved when enlisted. Pearson correlations (r) were calculated on the total range of T. gondii IgG titers, CES-D scores, PCL-M scores, and
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POMS scores, both total score and subscales. T. gondii IgG titers were significantly correlated with the POMS-depression subscale, r = 0.245, n = 70, p < 0.05; POMS-confusion/ bewilderment subscale, r = 0.242, n = 70, p < 0.05; and POMS-total subscale, r = 0.292, n = 70, p < 0.05; and were also correlated significantly with the CES-D scores, r = 0.224, p < 0.05. Although these results are significant, the effects appear to be small. To analyze the differences in mood disturbance between positive and negative women, r-tests were conducted com paring these two groups. Seropositive participants had sig nificantly higher POMS-depression scores (t (68) = 2.35, p < 0.05) with an effect size (rj2) of 0.08, higher POMStension scores (t (68) = 2.06, p < 0.05, t f = 0.06), and higher POMS-anger scores (t (68) = 2.18, p < 0.05, rf = 0.07). The CES-D score was significantly higher in seroposi tive women (t (68) = 2.68, p = 0.026, t f = 0.09). There were no significant differences in PCL-M scores between the 2 groups. Cronbach a was calculated for each instrument analyzed in this study and there was an evidence of good to excellent internal consistency in these data (CES-D = 0.90, PCL = 0.96, POMS depression = 0.94, POMS tension = 0.93, POMS anger = 0.94, POMS confusion = 0.74, POMS fatigue = 0.94, POMS total = 0.91).
DISCUSSION The purpose of this study was to examine the relationships between sociodemographic variables, deployment, mood, depression, PTSD symptoms, and T. gondii IgG antibody titer. There is almost no literature about incidence, risk fac tors, and effects of T. gondii infection in military populations, especially in women Veterans. However, military recruits were measured for T. gondii IgG titer in 196241 and again in 198 942 as a general proxy for U.S. population levels. Smith et al42 reported a decrease in seropositivity for T. gondii by one-third over the past 27 years in these not-yet-deployed military recruits. Previous studies support our findings of relationships between T. gondii antibody titer and psychiatric symptoms and behavior. Several studies show that suicide attempters had significantly higher T. gondii IgG antibody titers4,8,15’43' 45 T. gondii seroprevalence has also been recently reported to be related to bipolar disorder." Groer et al'° reported a posi tive correlation of T. gondii IgG antibody titer with POMSdepression and POMS-anxiety subscale scores in a sample of 414 pregnant women, 44 of whom were seropositive for T. gondii infection. Amminger et al46 reported in 105 partic ipants a high risk for psychosis that higher levels of T. gondii IgG antibodies were significantly associated with more severe positive psychotic symptoms. T. gondii infection has also been linked to psychiatric disorders such as schizophrenia47 and bipolar disorder." The relationships between T. gondii and depressive symptoms, anger, confusion, and overall mood disturbance
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that were found in this study are particularly important because it has been reported that individuals infected by T. gondii have a higher risk of suicidal behavior. This rela tionship is troubling, particularly in Veterans, as they have an increased risk for suicide. With the number of suicides increasing annually across all branches of the military, both in active duty service members and in Veterans, the role of T. gondii infections deserves further exploration. Potential explanations must be considered in regard to the relationships between T. gondii and mood disturbance. Per haps depression and dysphoria lead to behaviors such as poor hygiene habits that can increase exposure and infection. In addition, genetic differences in susceptibilities may be involved.48 Some studies suggest that the T. gondii link with depression is only present in bipolar disease and not unipolar depression. 11 There may be corelationships of T. gondii infection with other neurotropic organisms. Nevertheless the remarkable relationships we have observed underscore the interest for further exploration with larger sample sizes. Hence, a larger sample size recruited from a broader geo graphical area will be needed to add additional power and allow generalizing of the results more widely. Similarly, it would be important to include male Veterans in further stud ies as well. Recruitment of participants in this study (women Veterans’ event and personal contacts) posed a risk of poten tial selection bias. The association of mood disturbance and depression with T. gondii IgG titer in this small sample sup ports the neuroinflammation hypothesis; however, inflamma tory markers were not measured to test that relationship. The low number of women Veterans who were seroposi tive for T. gondii reduced the ability to control for age and ethnicity. Titers below the cut point for seropositivity may indicate resolved infection in the distant past and this was not possible to evaluate. Current latent infection with T. gondii was most prevalent in women who had been deployed to foreign countries. Future follow-up studies to further investi gate the results of this study should include larger sample sizes, younger age distribution with recent deployment to Iraq and Afghanistan, measurement of both IgG and IgM titers including antibody affinity and serotyping to determine timing and source of infection, longitudinal sampling of individuals, examination of lifestyle factors (diet, exposure to feral cats, hygiene) of individuals while deployed, and appropriate demographic controls, as well as, potentially, functional neuroimaging and neuropsychological testing. ACKNOWLEDGMENTS This material is based on the work supported by the Office of Research and Development, Health Services R&D Service, Department of Veterans Affairs (RRP 06-151). We are extremely grateful to the women Veterans who par ticipated in this study. We are also grateful for the students and faculty who volunteered their time at the Women Veterans’ Day of Recognition held on November 2011 as well as the laboratory staff at the University of South Florida College of Nursing Biobehavioral laboratory. This article was devel oped through grant funding support from Research to Improve Emotional Health and Quality of Life Among Service Members with Disabilities
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(RESTORE LIVES) Department of the Army grant number W81XWH-101-0719. The sponsors had no role in the collection of study data or preparation, review, or approval of the manuscript. Dr. Brenner's and Dr. Postolache’s contributions were supported by the Rocky Mountain MIRECC, VISN 19, Denver, CO. Additionally, Dr. Postolache was sup ported by the American Foundation for Suicide Prevention (Distinguished Investigator Award).
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